Many potential drug candidates are withdrawn from further development because their promising in vitro results do not translate into therapeutic efficacy during clinical trials. Because the time and cost of taking a compound into clinical trials can be as much as ten years and 200 million dollars, failure of a potential drug at the clinical phase is enormous.
For potential drug candidates that act as receptor agonists, receptor desensitization may contribute to the disconnect between in vitro potency and lack of clinical efficacy. Receptor desensitization typically occurs upon continued stimulation of the receptors with agonists. When receptors are initially exposed to an agonist, the initial response usually peaks and then decreases to some tonic level. If the agonist is removed for a brief period, this state of receptor desensitization is maintained such that a second addition of the agonist provokes a diminished response. Removal of the agonist for a more extended period of time generally allows the receptors to reset its capacity for maximal response.
There are two types of desensitization: homologous and heterologous desensitization. Homologous desensitization is defined as the reduced response of a receptor induced only by the agonist that has stimulated the receptor. Heterologous desensitization is defined as the reduced response of a receptor induced by something other than the agonist for that receptor. For example, receptors for different hormones that act on a single signaling pathway may become less effective when only one of the receptors is continuously stimulated. Such heterologous desensitization may result either from modification of each receptor by a common feedback mechanism or from effects exerted at some common point in the effector pathway distal to the receptor itself.
Despite the importance of receptor desensitization, drug discovery efforts generally focus on agonist potency. However, because receptor desensitization can have a profound effect on clinical efficacy, methods for evaluating and incorporating receptor desensitization for therapeutic uses are needed and desired.